The overall goal of this project is to understand how complications of sickle cell disease affect pulmonary pulsatile hemodynamics and right ventricular function. Sickle cell disease is one of the most common heritable monogenetic disease in the world. Pulmonary hypertension as emerged as a leading cause of morbidity and mortality among patients with sickle cell disease. The mechanisms by which pulmonary hypertension develops in patients with sickle cell disease remains unclear. Multiple pathways have been proposed including increased red blood cell stiffness, hyperviscosity, hypoxemia, hemolysis, reperfusion injury and pulmonary embolism. However, the mechanical mechanisms and resulting hemodynamic changes, by which pulmonary hypertension develops in patients with sickle cell disease has not been explored in depth. The investigation of pulmonary pulsatile hemodynamics in pulmonary hypertension alone, has revealed that changes in arterial stiffness affect right ventricular afterload, and have been shown to better predict mortality in these patients. While patients with sickle cell disease have been shown to have increased arterial stiffness systemically, the stiffness of either the proximal or distal pulmonary arteries has not been explored in depth. The first two aims proposed will focus on how changing red blood cell stiffness, hypoxemia and hyperviscosity contribute to changes in pulmonary pulsatile hemodynamics. The third aim will measure changes in both right ventricular afterload, including changes in pulmonary arterial stiffness, and right ventricular function in mice with pulmonary hypertension associated with sickle cell disease. This project would be the first to investigate pulmonary pulsatile hemodynamics, right ventricular function, and ventricular-vascular interactions in the context of pulmonary hypertension associated with sickle cell disease. Our results will lend valuable insight into how sickle cell disease affects pulmonary pulsatile hemodynamics and contributes to the high rates of mortality in patients with pulmonary hypertension and sickle cell disease.